Research into new therapeutic strategies for treating pediatric solid tumors has focused on bone and soft-tissue sarcomas including the Ewings sarcoma family of tumors, rhabdomyosarcoma, and osteosarcoma. These sarcomas serve as an excellent "model system" for the exploration of strategies and hypotheses with broad applicability to both pediatric and adult oncology. The overall goal of these protocols is to improve our use of known active agents through dose-intensification and reduction in toxicity. Recently, strategies have also been developed to identify highly active new agents with novel mechanisms of action in previously untreated, poor-prognosis patients, as well as to identify methods of drug administration which may overcome intrinsic or acquired drug resistance. Previous Pediatric Branch protocols demonstrated high activity for intensive vincristine, doxorubicin, and cyclophosphamide (VAdriaC) in newly diagnosed sarcoma patients (83-C-73H), and a high level of activity for ifosfamide and etoposide (lE) in those with recurrent tumors (85-C- 154). The results of our recently completed pilot sarcoma protocol (86-C- 169), which integrated IE into the up-front treatment of patients along with VAdriaC, suggested a modest improvement in outcome for patients with localized tumors, but no improvement for those with metastatic disease. Two companion phase III studies attempted to ameliorate the major toxicities of this regimen. Use of rh-GM-CSF produced a modest reduction in the duration of severe neutropenia, however, this benefit was not demonstrated in the majority of patients receiving the growth factor, did not translate into reductions in infectious complications or supportive care requirements, and was offset by a greater degree and duration of thrombocytopenia (88-C-165). Use of ICRF-187 permitted the more safe administration of doxorubicin with no adverse impact on non-cardiac toxicities, response to chemotherapy, or survival (89-C-07). These companion studies were the only randomized trials of these promising new approaches in pediatric solid tumor patients. Our current front-line sarcoma protocol (93-C-0125) builds upon the results of the previous two generations of sarcoma studies. It is assessing the activity of new agents with novel mechanisms of action in newly diagnosed patients in a phase II "window" design, is dose intensifying the use of doxorubicin and cyclophosphamide, and is piloting the use of peripheral blood progenitor cells as a means of permitting dose-escalation and dose-intensification of IE plus melphalan.